Arizona Cancer Therapeutics LLC (ACT) proposes a two-year, preclinical research project in cooperation with the University of Arizona Cancer Center to develop the novel anti-tumor therapeutic, Protein transduction domain-MUC1 Inhibitory Peptide (PMIP). PMIP is an intracellular MUC1 peptide that acts as a decoy to block the MUC1- oncoprotein interactions that drive breast cancer growth and metastasis. Utilizing a protein transduction domain to allow for transmembrane cellular uptake, PMIP can freely enter the cell and interact with intracellular target proteins. Laboratory research at the University of Arizona over the past nine years has examined the ability of MUC1 and an oncogenic partner, epidermal growth factor receptor (EGFR), to synergistically drive breast cancer progression. To block these tumor-specific, intracellular interactions, the first-in-class peptide-based cancer therapeutic, PMIP, was developed. Studies in tumor-bearing mouse models demonstrate that PMIP blocks tumor growth and metastasis and is nontoxic and tumor specific, making it an excellent anti-tumor drug candidate to carry forward through preclinical studies and clinical trials. Over 40,000 Americans die annually from metastatic breast cancer and, in greater than 90 percent of human breast carcinomas and metastases, MUC1 is over-expressed. This project represents critical steps in preclinical studies in drug dosing, absorption, distribution, metabolism and toxicity. The project will also investigate the benefits of PMIP when used in combination with FDA-approved chemotherapies for breast cancer. PMIP represents a unique approach to targeting MUC1 activities in cancer - other clinical trials targeting MUC1 have been designed to elicit anti-MUC1 immunity, and have been largely ineffective. Unlike these approaches, PMIP does not rely on activation of the immune response, but instead directly blocks tumor-promoting intracellular interactions. If successful, PMIP can substantially enhance the effective treatment options for metastatic breast cancer patients. This project aligns to NIH's mission to enhance health, lengthen life, and reduce the burdens of illness and disability by researching a new and unique anti-tumor drug to treat, effectively and with low or no toxicity, metastatic breast cancer.